This twin study Component will provide crucial information on the heritability of phenotypes being studied, the generality versus specificity of heritable vulnerability, and genetic and environmental contributions to developmental persistence of these patterns of behavior. Identifying maximally heritable phenotypes for vulnerability to antisocial drug dependence will maximize the likelihood of a successful search for QTLs. Studying the mediation of genetic influences, including those of QTLs, during behavioral development is necessary for understanding how genes influence vulnerability. To achieve this, we now propose to extend our augmented twin study to understand how genes and environmental risks contribute to vulnerability to drug use, abuse and dependence as they develop during adolescence. We will have enrolled 1300 pairs of twins and their siblings aged 12 through 18 years into the study and have assessed them using the Center's core protocol. We will conduct a second wave of assessment at ages 17 through 23 years. We will test the following specific hypotheses: 1) Vulnerability to drug dependence in adolescence is predominantly a generalized phenomenon, with different substances acting as 'alternate forms'. In the absence of persistent antisocial behavior, risk factors become more substance specific in later adolescence and early adulthood. Antisocial behavior is a risk factor for persistent generalized risk. 1b) Both general and substance specific vulnerability are heritable, though different genetically influenced mechanisms are involved. 2) Persistent drug use that progresses to regular use, abuse, and dependence is a more heritable phenotype than transient drug use. 3) Individuals with persistent drug use, abuse, and symptoms of dependence are more likely to have comorbid symptoms of other psychiatric disorders, especially Conduct Disorder and Antisocial Personality Disorder. 3b) The source of the comorbidity between antisocial behavior and persistent drug use, abuse, and symptoms of dependence is largely genetic. 4) The genetic link between antisocial behavior and persistent and generalized drug use, abuse, and dependence, is mediated through a constellation of individual characteristics that have been characterized as behavioral disinhibition.